Centrosome instability as a mechanism to promote localized prostate cancer

项目摘要/摘要 在解释前列腺癌(PCa)的起源方面，我们的知识存在一个根本性的缺口。与许多不同的是 在癌症方面，PCA缺乏关键癌基因和肿瘤抑制基因的标志性突变，相反， 表现出大规模的基因组不稳定性。我们建议将亚细胞细胞器不稳定性作为一种 导致前列腺上皮细胞基因组不稳定的机制。具体地说，我们专注于 在中心体上，微小的细胞质细胞器极大地影响基因组的完整性。着丝粒可以 当它们被扩增时成为亚细胞致病原结构，就像在许多不同的 癌症，导致有丝分裂错误，基因组不稳定，并在小鼠模型中诱导肿瘤形成。 同样，中心体丢失会导致有丝分裂错误和基因组不稳定，这与中心体相同 扩增，但在癌症中尚未见报道。我们最近发现，人类前列腺 腺癌缺乏中心体，提供了一种新的机制解释基因组的不稳定性 PCA。我们的长期目标是发现前列腺癌发生背后的异常变化， 提高前列腺癌的诊断和治疗策略。这样做的目的是 应用是确定中心体丢失在驱动基因组不稳定中的贡献 并确定中心体消失的分子机制基础。摘自我们的 初步数据，我们的中心假设是缺氧是与生理相关的关键决定因素 前列腺的中心体丢失，进而刺激基因组的不稳定和肿瘤的发生。这个 这项拟议的研究的基本原理是解决一个具有挑衅性的问题，即癌症特异性如何在 亚细胞致病原结构(具体地说，中心体丢失)发泄并促成 致癌。这一假设将在三个具体目标中得到检验：1)确定中心体丢失 由前列腺细胞和肿瘤中的缺氧触发；2)确定中心体丢失是否驱动 正常前列腺上皮细胞中的基因组不稳定和促进肿瘤的发生；以及3)确定 中心体丢失是高级别前列腺上皮内瘤变(PIN，原位癌)的特征。 这种方法是创新的，因为它研究了一种新的亚细胞细胞器不稳定机制。 在前列腺癌发生过程中：具体地说，缺氧和中心体的生物发生是机械性的 在前列腺癌的形成中作为基因组不稳定性的驱动因素。这项拟议的研究具有重要意义 因为它测试了一个新的概念，即关键亚细胞器的丧失是导致前列腺癌的原因 基因组不稳定，这既是前列腺癌演变的标志，也是其诱因。如果我们是正确的， 中心体丢失将是人类前列腺癌发生早期的一个有形事件，为人类前列腺癌提供了新的 早期发现和治疗策略。

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in our knowledge to explain the origin of prostate cancer (PCa). Unlike many cancers, PCa lacks signature mutations in key oncogenes and tumor-suppressor genes and, instead, displays large-scale genomic instability. We propose to study subcellular organelle instability as a mechanism that results in genomic instability in epithelial cells of the prostate gland. Specifically, we focus on centrosomes, tiny cytoplasmic organelles that dramatically influence genome integrity. Centrosomes can become subcellular pathognomonic structures when they are amplified, as is the case in many different cancers, causing mitotic errors, genomic instability and inducing tumorigenesis in mouse models. Likewise, centrosome loss causes mitotic errors and genomic instability identical to centrosome amplification, but has not been reported in cancer. We discovered recently that human prostate adenocarcinoma lack centrosomes, providing a novel mechanistic explanation for genomic instability in PCa. Our long-term goal is to discover the abnormal changes that underlie prostate tumorigenesis, malignancy and recurrence, and to improve PCa diagnosis and treatment strategies. The objective of this application is to determine the contribution of centrosome loss in driving genomic instability resulting in PCa and to determine the molecular mechanistic basis for centrosome disappearance. Drawn from our preliminary data, our central hypothesis is that hypoxia is a key physiologically-relevant determinant of centrosome loss in the prostate which, in turn, stimulates genomic instability and tumorigenesis. The rationale for the proposed research is to address the provocative question of how cancer-specific changes in subcellular pathognomonic structures (specifically, centrosome loss) transpire and contribute to carcinogenesis. This hypothesis will be tested in three specific aims: 1) Determine whether centrosome loss is triggered by hypoxia in prostate cells and tumors; 2) Determine whether centrosome loss drives genomic instability in normal prostate epithelial cells and promotes tumorigenesis; and 3) Determine if centrosome loss is characteristic of high-grade prostatic intraepithelial neoplasia (PIN, carcinoma in situ). The approach is innovative because it investigates a novel mechanism of subcellular organelle instability during prostate tumorigenesis: specifically, that hypoxia and centrosome biogenesis are mechanistically coupled as drivers of genomic instability in prostate tumor formation. The proposed research is significant because it tests a new concept that the loss of a critical subcellular organelle is responsible for PCa genomic instability, which is both a hallmark and agent of prostate tumor evolution. If we are correct, centrosome loss will be a tangible event early in the genesis of human prostate cancer, providing new early detection and treatment strategies.